tbuckley/cabot-search huggingface dataset:
Abstract 4605: Chronic VEGF-C signaling exacerbates the progression of non-alcoholic steatohepatitis and hepatocarcinoma through endothelial VEGFR2 and VEGFR3
Authors: Seock-Won Youn, Jason W.-L. Eng, Bhairavi Swaminathan, Pamela Teneqexhi, Rahul Vadakath, Jan K. Kitajewski
Journal: Cancer Research (2023)

Abstract Obesity, aging, and metabolic diseases contribute to non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic steatohepatitis (NASH) due to ongoing inflammation and pathological angiogenesis. At present, NASH is a leading cause of cirrhosis, hepatocarcinoma cancer (HCC) and liver transplant within the United States. Pathological angiogenesis of liver sinusoidal endothelial cells (LSECs) is one of the hallmarks of liver injury that disrupt normal LSEC physiology. Therefore, strategies which target factors involved in LSEC dysregulation may improve the progression of hepatic diseases. Examination of a human tissue microarray identified increased levels of vascular endothelial growth factor-C (VEGF-C) in NASH livers compared with healthy individuals. Additionally, single nuclei RNA sequencing and immunofluorescent staining revealed that the receptors for VEGF-C, VEGFR2 and VEGFR3, are primarily expressed by the LSECs. Using murine models of NASH, we further investigated the role of VEGF-C during disease progression. Chronic over expression of VEGF-C by adeno-associated viral (AAV) infection in mice fed a western diet with carbon tetrachloride injections increased NASH progression compared with control AAV infected NASH mice. Interestingly, overexpression of VEGF-C C156S, a variant of VEGF-C which exclusively binds to VEGFR3, resulted in significantly increased hepatic steatosis, but only minimal fibrosis. To determine whether blockade of VEGF-C signaling would delay disease progression, we administered lenvatinib, a tyrosine kinase inhibitor which primarily blocks VEGFR2 and VEGFR3 at low doses, to NASH mice. We discovered that low dose lenvatinib resulted in significantly decreased amount of fibrosis, steatosis, and tumor formation. Analysis of vehicle treated and lenvatinib treated livers by single nuclei RNA sequencing uncovered significant changes in endothelial cell genes associated with extracellular interactions and inflammation, as well as hepatocyte genes involved in lipid synthesis and metabolism. Taken together, these findings indicate that chronic VEGF-C production in NASH plays a role in promoting liver fibrosis and steatosis as well as HCC development, and that blockade of the downstream receptors for VEGF-C, VEGFR2 and VEGFR3, may be a promising therapeutic strategy to mitigate disease severity. Citation Format: Seock-Won Youn, Jason W.-L. Eng, Bhairavi Swaminathan, Pamela Teneqexhi, Rahul Vadakath, Jan K. Kitajewski. Chronic VEGF-C signaling exacerbates the progression of non-alcoholic steatohepatitis and hepatocarcinoma through endothelial VEGFR2 and VEGFR3. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4605.
Abstract 4601: Vitamin D supplementation attenuates resistance to anti-angiogenic therapy in colorectal cancer liver metastases
Authors: Miran Rada, Lucyna Krzywon, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Anthoula Lazaris, Peter Metrakos
Journal: Cancer Research (2023)

Abstract Colorectal cancer liver metastasis (CRCLM) is one of the deadliest cancers. CRCLM tumours have two distinct histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours are angiogenic, while their RHGP counterparts are vessel co-opting. The patients with RHGP tumours showed poor response to anti-angiogenic agents, as well as a worse prognosis. Herein, we conducted a retrospective cohort study that comprised 106 CRCLM patients to examine the effect of vitamin D supplementation on the HGPs of the tumours and the 5-year overall survival (OS). Interestingly, we found an inverse correlation between vitamin D supplementation and the presence of RHGP tumours in CRCLM patients. Additionally, the population who used vitamin D supplementation had significantly better 5-year OS. Moreover, our in vivo results suggested that vitamin D supplementation significantly improves the response of CRCLM tumours to anti-angiogenic therapy. Mechanistically, we found that vitamin D can suppress cancer cell motility, which is essential for the development of vessel co-option tumours and resistance to anti-angiogenic therapy. Collectively, this study suggests vitamin D supplementation is a promising way to attenuate resistance to anti-angiogenic therapy and improve the prognosis of CRCLM patients. Citation Format: Miran Rada, Lucyna Krzywon, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Anthoula Lazaris, Peter Metrakos. Vitamin D supplementation attenuates resistance to anti-angiogenic therapy in colorectal cancer liver metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4601.
Abstract 4602: Differences in tumor vascular density between smoker and non-smoker cancer patients
Authors: Shubhangi Singh, Mohammad Aslam Khan, Elba T. Herrera, Seema Singh, Ajay P. Singh, Santanu Dasgupta
Journal: Cancer Research (2023)

Abstract Smoking is among the most significant preventable risk factors associated with cancer and other benign diseases. Cancer development is a multi-step process in which transforming cells gradually gain malignant properties through a series of oncogenic genetic alterations. Successful cancer progression also depends on the remodeling of the surrounding stroma, which feeds the cancer cells in a host-parasite interaction. Tumor angiogenesis, the process of blood vessel formation, is an essential feature of solid tumors that ensures that they have the needed supply of food and oxygen to sustain their proliferative growth. We previously demonstrated that nicotine, an addictive component of tobacco smoke, promoted tumor angiogenesis by impacting the growth of endothelial cells. In the present work, we examined the differences in tumor vasculature between smoker and non-smoker patients to find clinical support for our laboratory findings. After searching the available tumor cases in the repository for the patient’s smoking history, I selected 27 smokers (12 lung and 15 prostate adenocarcinomas) and 19 non-smokers (4 lung and 15 prostate adenocarcinomas) cases. The tissue blocks were sectioned and subjected to hematoxylin and eosin staining and immunohistochemistry using an antibody against CD31, a biomarker for endothelial cells. Following digital scanning, all slides were reviewed to identify tumor areas and CD31+ tubular structures (blood vessels). We observed that lung and prostate tumor tissues from smoker patients had a significantly higher number of blood vessels than those from non-smoker patients. Thus, increased tumor vascularization appears to be a common feature of smoking cancer patients providing clinical support for a novel mechanism by which smoking may contribute to tumor pathobiology. Citation Format: Shubhangi Singh, Mohammad Aslam Khan, Elba T. Herrera, Seema Singh, Ajay P. Singh, Santanu Dasgupta. Differences in tumor vascular density between smoker and non-smoker cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4602.
Abstract 4611: Leveraging organotypic brain slice models to enhance adoptive cellular therapies
Authors: Alexandra Reid, Dan Jin, Bayli DiVita-Dean, Laura Falceto-Font, John Figg, Connor Francis, Catherine Flores
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is an incredibly aggressive and prevalent primary CNS tumor with dismal survival outcomes. GBM’s intra-tumor heterogeneity and lack of anti-tumor immune cell infiltration have proved to be formidable challenges to the development of effective therapies. These hurdles may be overcome by garnering a better understanding of the cell-cell interactions occurring within the tumor microenvironment (TME). Accounting for the complexity and the spatial orientation of the components within the TME may offer insight into the multitiered layers of immunosuppression capitalized on by GBM tumors, thus elucidating the factors responsible for poor response to therapy and uncovering potential therapeutic targets that may offer more favorable therapeutic results for immunotherapies. Current in vitro and in vivo models, however, sorely limit our ability to probe these distinct attributes while preserving the intricate nature of the TME. To bridge this gap, we have devised a novel organotypic brain slice culture (BSC) model using tumor-bearing C57BL/6J mice, allowing us to characterize the tumor milieu in situ. We have identified infiltration of myeloid-derived suppressor cells (MDSC) and microglia polarized to the M2 anti-inflammatory phenotype within the TME. Leveraging this platform, we sought to define further the factors contributing to the dynamic impacts of GBM immunosuppression, such as the tolerogenic response in dendritic cells (DC) upon interaction with the TME. We have demonstrated outcomes similar to those seen in vivo following the introduction of DCs to tumor-bearing BSCs, further supporting the physiological relevancy of this model, and have since worked to unravel elements responsible for this response. Citation Format: Alexandra Reid, Dan Jin, Bayli DiVita-Dean, Laura Falceto-Font, John Figg, Connor Francis, Catherine Flores. Leveraging organotypic brain slice models to enhance adoptive cellular therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4611.
Abstract 4252: CCNE1 amplification in high-grade serous ovarian cancer: analysis of the GENIE database
Authors: Ashaar Al-Akhras, Shaden Tashtoush, Alina Ghazou
Journal: Cancer Research (2023)

Abstract Background: High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer as well as the most lethal. A primary oncogenic driver in a subset of HGSOC patients, CCNE1 amplification is associated with poorer outcomes and resistance to standard treatment. This study aims to investigate the copy number gain of CCNE1 and the genetic mutations associated with CCNE1 amplification using a large cohort of clinico-genomic data. Methods: We queried the American Association of Cancer Research-Genomics Evidence Neoplasia Information Exchange (GENIE) registry database v12.1 for patients with HGSOC. We studied CCNE1 amplification and the clinical, demographic, and genetic mutation associations. Results: A total of 3297 HGSOC samples were extracted from the registry. The mean age of patients at sequencing was 62 ± 10 years. Out of 2416 samples profiled for copy number alterations, CCNE1 amplification was found in 13.6%, being the most commonly amplified gene, followed by AGO2 (11.7%) and MYC (9.7%). Co-amplification between CCNE1 and AKT2 was demonstrated. Between the 397 samples with CCNE1 amplification and 2088 without, the genes that were more frequently mutated in the CCNE1 amplified group were AKT2 (20.4% vs 3.2%, p&amp;lt;0.001), KRAS (11.3% vs 4.3%, p&amp;lt;0.001), BRD4 (8.0% vs 4.4%, p = 0.006), and ERBB2 (7.9% vs 4.0%, p = 0.003). Other genes were less frequently mutated in the CCNE1 amplified cohort such as NF1 (7.6 % vs 12.9%, p = 0.009), BRCA1 (3.7% vs 10.0%, p&amp;lt;0.001), BRCA2 (2.7% vs 7.4%, p = 0.003), RB1 (2.7% vs 6.4%, p = 0.013), and PTEN (1.2% vs 4.0%, p = 0.02). Frequencies of MYC, PIK3CA, KMT2D, CDK12, and TSC2 mutations were similar between the two groups. TP53 was mutated in 100% of samples. There were no significant differences between the two groups in primary race or total mutation count, and mean age at sequencing was similar. Conclusion: Somatic sequencing is warranted to identify patients of this subset of HGSOC, and understanding the co-amplifications and co-mutations is essential so that they are targeted for optimal survival outcomes. Citation Format: Ashaar Al-Akhras, Shaden Tashtoush, Alina Ghazou. CCNE1 amplification in high-grade serous ovarian cancer: analysis of the GENIE database. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4252.
Abstract 461: Targeting glucose metabolism in lung cancer
Authors: Sucheta Telang, Simone Chang, Nicole Sanders
Journal: Cancer Research (2023)

Abstract Positron emission tomographic studies with 2-18F-fluoro-deoxy-glucose (FDG-PET) consistently demonstrate that non-small cell lung cancers (NSCLC) take up significantly more glucose than normal lung. NSCLCs preferentially utilize glucose to support their rapid growth- a phenotype driven by several oncogenic alterations among which mutations of the oncoprotein Ras are frequently observed. Oncogenic Ras is shown to activate downstream effectors (e.g. HIF-1α) that stimulate glycolysis - in part by activation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase family of enzymes (PFKFB1-4). The PFKFBs produce fructose-2,6-bisphosphate (F26BP) which activates a key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK1). In preliminary studies, we found that the PFKFB4 family member was highly expressed relative to other PFKFB isoforms (by multiplex RT-PCR) in a series of patient-derived NSCLCs relative to paired normal lung tissue. We further explored PFKFB4 protein expression by immunohistochemistry in NSCLCs derived from a cohort of patients and found markedly elevated PFKFB4 in the majority of tumors relative to adjacent normal tissue. We then determined that silencing PFKFB4 markedly reduced F26BP, glycolysis and cell survival in NSCLC cell lines and inhibited xenograft lung tumor growth in vivo. In order to target PFKFB4, we conducted a virtual screen of compounds that fit into the active site of PFKFB4 and discovered a first-in-class small molecule selective PFKFB4 inhibitor, termed 5MPN, that selectively inhibits recombinant PFKFB4 activity and decreases F26BP, glycolysis and proliferation in multiple NSCLC cell lines, with significantly higher anti-proliferative effects in Ras-driven cell lines. 5MPN also caused marked suppression of growth in established NSCLC xenograft tumors, importantly without systemic toxicity. We have developed an inducible, pan-tissue homozygous floxed Pfkfb4 knockout mouse and crossed it with a Cre recombinase mouse driven by a tamoxifen-inducible β-actin promoter to produce Cre/Pfkfb4fl/fl mice. We crossed Cre/Pfkfb4fl/fl mice with a Ras-driven lung cancer model, induced Pfkfb4 deletion by tamoxifen administration and found significantly lower total lung tumor burden in these mice accompanied by decreased PFKFB4 expression in tumors and lung tissue. Taken together, these data provide strong rationale for the further evaluation of small molecule inhibitors of PFKFB4 as a potential therapeutic strategy against NSCLC. Citation Format: Sucheta Telang, Simone Chang, Nicole Sanders. Targeting glucose metabolism in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 461.
Abstract 4612: Microphysiological vascularized solid liver tumor model for drug and cell therapy
Authors: Jyothsna Vasudevan, Ragavi Vijayakumar, Jose Antonio Reales-Calderon, Maxine Sin Lam, Jin Rong Ow, Joey Aw, Damien Tan, Giulia Adriani, Andrea Pavesi
Journal: Cancer Research (2023)

Abstract Development of efficacious therapeutic strategies against solid tumors is limited by the lack of pre-clinical models that can reliably predict treatment outcomes in patients. This is primarily because models often do not accurately reflect the complexity of the tumor microenvironment (TME). The TME consists of vasculature, stromal cells and immune cells that can promote tumor resistance or prevent targeted drug and cell therapy. Here, we developed an in vitro vascularized liver tumor model in a microfluidic device to evaluate drug delivery and immunotherapy approaches. The model consists of a tumor spheroid surrounded by a perfusable self-organized vasculature bed with physiologically relevant permeability. Sorafenib (Nexavar) efficacy was evaluated by assessing tumor spheroid viability, quantified by the loss of fluorescence signal. The presence of vasculature showed enhanced cytotoxicity, highlighting the importance of tumor-vascular interactions for testing therapeutic efficacy. Engineered immune cells (chimeric antigen receptor (CAR) T-cell and transiently expressing T-cell receptors (TCR)) were introduced into the model to demonstrate immunotherapy validation. Our results showed that the engineered immune cells were more effective at infiltrating the tumor spheroid without a vasculature but were more cytotoxic in the presence of the vasculature. By removing the cultured microtissue from the device and performing digital spatial transcriptomics on standard paraffin-embedded sections, we identified known and novel genes involved in creating a pro-tumorigenic microenvironment. This platform can be utilized to model critical features of the in vivo TME, providing better predictability of drug responses, with potential applications towards personalized medicine. Citation Format: Jyothsna Vasudevan, Ragavi Vijayakumar, Jose Antonio Reales-Calderon, Maxine Sin Lam, Jin Rong Ow, Joey Aw, Damien Tan, Giulia Adriani, Andrea Pavesi. Microphysiological vascularized solid liver tumor model for drug and cell therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4612.
Abstract 4613: Inhibition of myosin II in triple-negative breast cancer cells limits macrophage recruitment in a 3D environment
Authors: Youngbin Cho, Ruxuan Li, Ioannis Zervantonakis
Journal: Cancer Research (2023)

Abstract Among all breast cancer subtypes, triple-negative breast cancer (TNBC) exhibits the least favorable outcomes with a complex tumor microenvironment that facilitates metastatic progression. Remodeling of the extracellular matrix at the tumor invasive front is associated with increased cancer cell motility and poor outcomes. Myosin II, a key cytoskeletal regulator, plays a central role in cancer cell metastatic potential. In the clinic, high expression of myosin II in breast tumors has been associated with distant metastasis and lower survival rates. Interestingly, breast tumors overexpressing myosin II exhibited a higher density of tumor-associated macrophages and an immunosuppressive microenvironment. However, the relationship between myosin II activation in TNBC cancer cells and macrophage recruitment remains poorly understood. Here we employed a novel 3D microfluidic model of tumor-macrophage co-culture to study macrophage infiltration toward cancer cells with high spatiotemporal resolution. Using a panel of TNBC cell lines we found that high myosin II expression in cancer cells correlated with higher macrophage recruitment in a 3D matrix. Pharmacologic or genetic inhibition of myosin II reduced macrophage recruitment. Furthermore, using our microfluidic devices, we controlled the spatial distribution of cancer cells in a 3D matrix and separated the role of cancer cell-secreted paracrine factors from cancer cell-mediated matrix remodeling on macrophage recruitment. Analysis of matrix remodeling over time revealed that targeting myosin II in cancer cells limited the establishment of migratory tracks that facilitated macrophage recruitment. In sum, our studies revealed the critical role of cancer cell-driven matrix remodeling in promoting macrophage infiltration that can be therapeutically targeted to reverse the establishment of an immunosuppressive microenvironment. Citation Format: Youngbin Cho, Ruxuan Li, Ioannis Zervantonakis. Inhibition of myosin II in triple-negative breast cancer cells limits macrophage recruitment in a 3D environment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4613.
Abstract 2623: Identification of KRAS suppressor genes: an ORFeome library screening
Authors: Christophe Marcireau, Philippine Furge, Fanny Sennechael, Alice Willart, Anne-Marie Blanchet, Veeranagouda Yaligara, Michel Didier, Frederic Lacroix, Melina Meunier, Laurent Debussches
Journal: Cancer Research (2023)

Abstract The RAS family genes encode small GTP-binding cytoplasmic proteins that are important signaling molecules. They regulate cell growth, survival and differentiation by coupling receptor activation to downstream effector pathways. Activating mutations of oncogenic RAS pathway genes are frequently detected in human cancers. KRAS is the most frequently mutated oncogene in human cancers. Most of these tumors are addicted to KRAS signaling. However, tumors can become resistant to RAS signaling pathway inhibitors through the activation of suppressor mechanisms. A possible explanation is that these tumors carry a second genomic perturbation that can compensate for the detrimental effects of the RAS signaling inhibitors, a phenomenon referred to as suppression. In model organisms, suppression interactions are generally divided into two classes: genomic suppressors which are secondary mutations in the genome that bypass a mutant phenotype, and dosage suppression interactions in which overexpression of a suppressor gene rescues a mutant phenotype. We decided to use the latter strategy in human cancer cells to identify KRAS suppressor genes. KRAS suppressor genes can be involved in resistance mechanisms of RAS pathway inhibitors and this approach could identify new targets for drug research programs and/or novel drug combinations. In this study we performed a screen on a human Open Reading Frame library (hORFeome collection) to identify potential KRAS suppressor genes. First, we engineered a SW620 cell line with a conditional expression of KRAS G12V by replacing the KRAS endogenous promoter by the doxycycline regulated TREG3 promoter. Second, we transduced this conditional cell line with a human ORFeome collection, and we looked for suppressors among the transduced cells that lead to cell proliferation in absence of KRAS G12V protein. Then candidate suppressors have been identified by NGS and validated after individual cloning and expression in SW620 KRAS conditional cells. Finally, two transcription factors and two orphan G protein-coupled receptors have been validated as KRAS suppressor genes when they are highly expressed. Citation Format: Christophe Marcireau, Philippine Furge, Fanny Sennechael, Alice Willart, Anne-Marie Blanchet, Veeranagouda Yaligara, Michel Didier, Frederic Lacroix, Melina Meunier, Laurent Debussches. Identification of KRAS suppressor genes: an ORFeome library screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2623.